In adult life, normal bone metabolism involves a balance between osteoclast-mediated resorption and osteoblast-mediated formation. This balance, referred to as coupling, maintains overall bone mass throughout early adult life. Most diseases relating to the skeletal system, such as metabolic (osteoporosis, renal osteodystrophy, Paget's, osteoarthritis), inherited (osteogenesis imperfecta, osteopetrosis), infectious (periodontal disease) and tumor-based (osteosarcoma, giant cell tumor), involve abnormalities in the resorption-formation coupling of bone remodeling. Bone resorption rates are determined by both the number and activity of osteoclasts. A number of hormonal signals may influence osteoclast recruitment, differentiation, and/or activity either directly or indirectly. Clinically, osteoclast dysfunction is a major factor in postmenopausal osteoporosis. The significant hormonal changes which begin with the onset of menopause are most likely implicated in osteoporosis. The principal investigator has recently identified the presence of estrogen receptor mRNA and functional receptors in isolated avian osteoclasts and demonstrated direct regulation of osteoclastic bone resorption. The objective of the proposed studies is to expand the previously reported direct influence of estrogen on avian osteoclast-mediated bone resorption to include mammalian estrogen responses and to identify some of the cellular effectors which mediate this response. The specific aims of these proposed studies are to: 1) identify estrogen receptors in avian osteoclasts and human giant cell tumors, 2) quantitate and characterize the effects of estrogen on avian, rat and human osteoclast resorptive activity, 3) assess the effects of estrogen on gene expression of selected osteoclast proteins which have been implicated in the resorption process, 4) assess the influence of estrogen on selected osteoclast protein levels and/or activity. Isolated avian osteoclasts, human osteoclasts and osteoclastomas, and rat osteoclasts will be challenged with estrogen to study the influence of steroid hormones on bone resorption. Gene expression influences (mRNA, protein levels, and enzyme activity) will be examined in avian osteoclasts and human osteoclastomas in vitro.